The overall goal of this program project is to discover and develop effective chemopreventative agents against lung and esophageal cancer, two important cancer types in the United States for which five year survival rates are very low. Our approach is to develop chemopreventative agents based on an understanding of the mechanisms by which they prevent tumor development. Under the support of the cooperative agreement that preceded this program project, we have established isothiocyanates are outstanding inhibitors of lung and esophageal cancer in animal models. The mechanisms of inhibition have ben elucidated and parallels between animals and humans noted. One compound developed by us-phenyl isothiocyanate (PEITC)-has been selected by NCI for phase I studies. In the current application, we will extend our studies on the development of isothiocyanates and their conjugates as chemopreventative agents for tobacco related cancers. Project 1, "Conjugates of Isothiocyanates as Chemopreventive Agents" will focus on the development of these compounds for chemoprevention of lung cancer, and will elucidate the relevant mechanisms. Collaborative studies with Projects 2 and 3 will examine toxicity, metabolism, and efficacy of isothiocyanate conjugates. Project 2, "Inhibitions of Esophageal Squamous Cell Carcinoma" will investigate the mechanisms by which isothiocyanates and their conjugates inhibit esophageal cancer and will discover suppressing agents to be used together with isothiocyanates. In collaboration with Projects 1 and 3, they will extend their exciting recent results on inhibition of N'-nitrosonornicotine induced esophageal carcinogenesis by 3-phenylpropyl isothiocyanate. Project 3, lung tumorigenesis by polycyclic aromatic hydrocarbons and the mechanisms by which mixtures of isothiocyanates inhibit lung tumor induction by tobacco smoke carcinogens in rodents; these studies will then be extended to humans who consume vegetables as sources of isothiocyanates. Project 3 will collaborate with Projects 1 and 2 in these studies. The Management Core will provide administrative, biostatistical, and advisory support to all projects. Our overall hypothesis is that isothiocyanates and their conjugates will decrease DNA damages by tobacco related carcinogens and will therefore by effective chemopreventive agents against lung and esophageal cancer.